tbuckley/cabot-search huggingface dataset:
N-cadherin protects oral cancer cells from NK cell killing in the circulation by inducing NK cell functional exhaustion via the KLRG1 receptor
Authors: Chao Lou, Kailiu Wu, Jianbo Shi, Zhenlin Dai, Qin Xu
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Circulating tumor cells (CTCs) can survive in the circulation and return to primary tumors through a self-seeding process. However, the mechanisms underlying CTCs escape from natural killer (NK) cell-mediated immune surveillance remain unclear. Method Self-seeded tumor cells were isolated and characterized using a modified contralateral seeding model. A comparison of transcriptional profiles was performed between the parental cells and self-seeded cells. The molecular mechanism of self-seeded tumor cells escaping from NK cell was demonstrated through in vitro experiments and verified in a CTC-mimicking in vivo model. Then, the expression level of key protein mediating CTCs immune escape was detected in 24 paired primary and recurrent tumor samples of patients with oral cancer by the immunohistochemical method. Result Self-seeded cells displayed resistance to NK cell-mediated lysis and a higher tumor seeding ability than their parental cells. Elevated expression levels of the CDH2 gene and its protein product, N-cadherin were found in self-seeded cells. NK cells secreted cytokines, and fluid shear stress facilitated N-cadherin release by promoting A disintegrin and metalloprotease 10 (ADAM10) translation or converting the precursor ADAM10 to the mature form. Soluble N-cadherin triggered NK cell functional exhaustion by interacting with the killer cell lectin-like receptor subfamily G member 1 (KLRG1) receptor and therefore protected tumor cells from NK cell killing in the circulation. In vivo experimental results showed that overexpression of N-cadherin promoted tumor self-seeding and facilitated the survival of CTCs. Compared with primary tumors, N-cadherin expression was significantly increased in matched recurrent tumor tissues. Conclusion Together, our findings illustrate an unknown mechanism by which CTCs evaded NK cell-mediated immune surveillance, and indicate that targeting N-cadherin is an effective strategy to prevent CTCs from homing to primary tumor.
Intraperitoneal Monocytes plus IFNs as a Novel Cellular Immunotherapy for Ovarian Cancer: Mechanistic Characterization and Results from a Phase I Clinical Trial
Authors: Daniel S. Green, Franklin Ning, Anna Duemler, Timothy G. Myers, Kathryn Trewhitt, Irene Ekwede, Ann McCoy, Nicole Houston, Jung-min Lee, Stanley Lipkowitz, Alexandra Zimmer, Miroslava Pavelova, Erin N. Villanueva, Leslie Smith, Andrew Blakely, Yovanni Casablanca, Steven L. Highfill, David F. Stroncek, Naoza Collins-Johnson, Sandhya Panch, JoLynn Procter, Chauha Pham, Soumya Korrapati, Steven M. Holland, Lindsey B. Rosen, Ana T. Nunes, Kathryn C. Zoon, Christopher B. Cole, Christina M. Annunziata
Journal: Clinical Cancer Research (2022)

Ovarian cancer is the most lethal gynecologic cancer and intrinsically resistant to checkpoint immunotherapies. We sought to augment innate immunity, building on previous work with IFNs and monocytes.Preclinical experiments were designed to define the mechanisms of cancer cell death mediated by the combination of IFNs α and γ with monocytes. We translated these preclinical findings into a phase I trial of autologous IFN-activated monocytes administered intraperitoneally to platinum-resistant or -refractory ovarian cancer patients.IFN-treated monocytes induced caspase 8-dependent apoptosis by the proapoptotic TRAIL and mediated by the death receptors 4 and 5 (DR4 and DR5, respectively) on cancer cells. Therapy was well tolerated with evidence of clinical activity, as 2 of 9 evaluable patients had a partial response by RECIST criteria, and 1 additional patient had a CA-125 response. Upregulation of monocyte-produced TRAIL and cytokines was confirmed in peripheral blood. Long-term responders had alterations in innate and adaptive immune compartments.Given the mechanism of cancer cell death, and the acceptable tolerability of the clinical regimen, this platform presents a possibility for future combination therapies to augment anticancer immunity. See related commentary by Chow and Dorigo, p. 299.
Cell Competition Shapes Metastatic Latency and Relapse
Authors: Kangsan Kim, Huocong Huang, Pravat Kumar Parida, Lan He, Mauricio Marquez-Palencia, Tanner C. Reese, Payal Kapur, James Brugarolas, Rolf A. Brekken, Srinivas Malladi
Journal: Cancer Discovery (2022)

Abstract Cell competition, a fitness-sensing process, is essential for tissue homeostasis. Using cancer metastatic latency models, we show that cell competition results in the displacement of latent metastatic (Lat-M) cells from the primary tumor. Lat-M cells resist anoikis and survive as residual metastatic disease. A memodeled extracellular matrix facilitates Lat-M cell displacement and survival in circulation. Disrupting cell competition dynamics by depleting secreted protein and rich in cysteine (SPARC) reduced displacement from orthotopic tumors and attenuated metastases. In contrast, depletion of SPARC after extravasation in lung-resident Lat-M cells increased metastatic outgrowth. Furthermore, multiregional transcriptomic analyses of matched primary tumors and metachronous metastases from patients with kidney cancer identified tumor subclones with Lat-M traits. Kidney cancer enriched for these Lat-M traits had a rapid onset of metachronous metastases and significantly reduced disease-free survival. Thus, an unexpected consequence of cell competition is the displacement of cells with Lat-M potential, thereby shaping metastatic latency and relapse. Significance: We demonstrate that cell competition within the primary tumor results in the displacement of Lat-M cells. We further show the impact of altering cell competition dynamics on metastatic incidence that may guide strategies to limit metastatic recurrences. This article is highlighted in the In This Issue feature, p. 1
Higher sensitivity monitoring of reactions to COVID-19 vaccination using smartwatches
Authors: Grace Guan, Merav Mofaz, Gary Qian, Tal Patalon, Erez Shmueli, Dan Yamin, Margaret L. Brandeau
Journal: npj Digital Medicine (2022)

Abstract More than 12 billion COVID-19 vaccination shots have been administered as of August 2022, but information from active surveillance about vaccine safety is limited. Surveillance is generally based on self-reporting, making the monitoring process subjective. We study participants in Israel who received their second or third Pfizer BioNTech COVID-19 vaccination. All participants wore a Garmin Vivosmart 4 smartwatch and completed a daily questionnaire via smartphone. We compare post-vaccination smartwatch heart rate data and a Garmin-computed stress measure based on heart rate variability with data from the patient questionnaires. Using a mixed effects panel regression to remove participant-level fixed and random effects, we identify considerable changes in smartwatch measures in the 72 h post-vaccination even among participants who reported no side effects in the questionnaire. Wearable devices were more sensitive than questionnaires in determining when participants returned to baseline levels. We conclude that wearable devices can detect physiological responses following vaccination that may not be captured by patient self-reporting. More broadly, the ubiquity of smartwatches provides an opportunity to gather improved data on patient health, including active surveillance of vaccine safety.
Immune dysfunction signatures predict outcomes and define checkpoint blockade–unresponsive microenvironments in acute myeloid leukemia
Authors: Sergio Rutella, Jayakumar Vadakekolathu, Francesco Mazziotta, Stephen Reeder, Tung-On Yau, Rupkatha Mukhopadhyay, Benjamin Dickins, Heidi Altmann, Michael Kramer, Hanna A. Knaus, Bruce R. Blazar, Vedran Radojcic, Joshua F. Zeidner, Andrea Arruda, Bofei Wang, Hussein A. Abbas, Mark D. Minden, Sarah K. Tasian, Martin Bornhäuser, Ivana Gojo, Leo Luznik
Journal: Journal of Clinical Investigation (2022)

Background. Immune exhaustion and senescence are dominant dysfunctional states of effector T cells and major hurdles for the success of cancer immunotherapy. In the current study, we characterized how acute myeloid leukemia (AML) promotes the generation of senescent-like CD8+ T cells and whether they have prognostic relevance.
Analysis of Insulin Resistance Among Children and Adolescents in Slovenia With Hypercholesterolemia After Treatment With Statins
Authors: Urh Groselj, Jaka Sikonja, Matej Mlinaric, Primoz Kotnik, Tadej Battelino, Joshua W. Knowles
Journal: JAMA Network Open (2022)

This cohort study assesses the association between short-term treatment with rosuvastatin therapy and changes in insulin resistance markers among children and adolescents in Slovenia who have hypercholesterolemia.
Temperature impacts on hate speech online: evidence from 4 billion geolocated tweets from the USA
Authors: Annika Stechemesser, Anders Levermann, Leonie Wenz
Journal: The Lancet Planetary Health (2022)

BackgroundA link between weather and aggression in the offline world has been established across a variety of societal settings. Simultaneously, the rapid digitalisation of nearly every aspect of everyday life has led to a high frequency of interpersonal conflicts online. Hate speech online has become a prevalent problem that has been shown to aggravate mental health conditions, especially among young people and marginalised groups. We examine the effect of temperature on the occurrence of hate speech on the social media platform Twitter and interpret the results in the context of the interlinkage between climate change, human behaviour, and mental health.MethodsIn this quantitative empirical study, we used a supervised machine learning approach to identify hate speech in a dataset containing around 4 billion geolocated tweets from 773 cities across the USA between May 1, 2014 and May 1, 2020. We statistically evaluated the changes in daily hate tweets against changes in local temperature, isolating the temperature influence from confounding factors using binned panel-regression models.FindingsThe prevalence of hate tweets was lowest at moderate temperatures (12 to 21°C) and marked increases in the number of hate tweets were observed at hotter and colder temperatures, reaching up to 12·5% (95% CI 8·0–16·5) for cold temperature extremes (–6 to –3°C) and up to 22·0% (95% CI 20·5–23·5) for hot temperature extremes (42 to 45°C). Outside of the moderate temperature range, the hate tweets also increased as a proportion of total tweeting activity. The quasi-quadratic shape of the temperature–hate tweet curve was robust across varying climate zones, income quartiles, religious and political beliefs, and both city-level and state-level aggregations. However, temperature ranges with the lowest prevalence of hate tweets were centred around the local temperature mean and the magnitude of the increases in hate tweets for hot and cold temperatures varied across the climate zones.InterpretationOur results highlight hate speech online as a potential channel through which temperature alters interpersonal conflict and societal aggression. We provide empirical evidence that hot and cold temperatures can aggravate aggressive tendencies online. The prevalence of the results across climatic and socioeconomic subgroups points to limitations in the ability of humans to adapt to temperature extremes.FundingVolkswagen Foundation.
Maternal Cardiac Changes in Women With Obesity and Gestational Diabetes Mellitus
Authors: Sharmaine Thirunavukarasu, Faiza Ansari, Richard Cubbon, Karen Forbes, Chiara Bucciarelli-Ducci, David E. Newby, Marc R. Dweck, Oliver J. Rider, Ladislav Valkovič, Christopher T. Rodgers, Damian J. Tyler, Amrit Chowdhary, Nicholas Jex, Sindhoora Kotha, Lara Morley, Hui Xue, Peter Swoboda, Peter Kellman, John P. Greenwood, Sven Plein, Thomas Everett, Eleanor Scott, Eylem Levelt
Journal: Diabetes Care (2022)

OBJECTIVE We investigated if women with gestational diabetes mellitus (GDM) in the third trimester of pregnancy exhibit adverse cardiac alterations in myocardial energetics, function, or tissue characteristics. RESEARCH DESIGN AND METHODS Thirty-eight healthy, pregnant women and 30 women with GDM were recruited. Participants underwent phosphorus MRS and cardiovascular magnetic resonance for assessment of myocardial energetics (phosphocreatine [PCr] to ATP ratio), tissue characteristics, biventricular volumes and ejection fractions, left ventricular (LV) mass, global longitudinal shortening (GLS), and mitral in-flow E-wave to A-wave ratio. RESULTS Participants were matched for age, gestational age, and ethnicity. The following data are reported as mean ± SD. The women with GDM had higher BMI (27 ± 4 vs. 33 ± 5 kg/m2; P = 0.0001) and systolic (115 ± 11 vs. 121 ± 13 mmHg; P = 0.04) and diastolic (72 ± 7 vs. 76 ± 9 mmHg; P = 0.04) blood pressures. There was no difference in N-terminal pro-brain natriuretic peptide concentrations between the groups. The women with GDM had lower myocardial PCr to ATP ratio (2.2 ± 0.3 vs. 1.9 ± 0.4; P &amp;lt; 0.0001), accompanied by lower LV end-diastolic volumes (76 ± 12 vs. 67 ± 11 mL/m2; P = 0.002) and higher LV mass (90 ± 13 vs. 103 ± 18 g; P = 0.001). Although ventricular ejection fractions were similar, the GLS was reduced in women with GDM (−20% ± 3% vs. −18% ± 3%; P = 0.008). CONCLUSIONS Despite no prior diagnosis of diabetes, women with obesity and GDM manifest impaired myocardial contractility and higher LV mass, associated with reductions in myocardial energetics in late pregnancy compared with lean women with healthy pregnancy. These findings may aid our understanding of the long-term cardiovascular risks associated with GDM.
Efficacy and safety of cilta-cel in patients with progressive multiple myeloma after exposure to other BCMA-targeting agents
Authors: Adam D. Cohen, María-Victoria Mateos, Yael C. Cohen, Paula Rodriguez-Otero, Bruno Paiva, Niels W. C. J. van de Donk, Thomas Martin, Attaya Suvannasankha, Kevin C. De Braganca, Christina Corsale, Jordan M. Schecter, Helen Varsos, William Deraedt, Liwei Wang, Martin Vogel, Tito Roccia, Xiaoying Xu, Pankaj Mistry, Enrique Zudaire, Muhammad Akram, Tonia Nesheiwat, Lida Pacaud, Irit Avivi, Jesus San-Miguel
Journal: Blood (2022)

B-cell maturation antigen (BCMA)-targeting therapies, including bispecific antibodies (BsAbs) and antibody-drug conjugates (ADCs), are promising treatments for multiple myeloma (MM), but disease may progress after their use. CARTITUDE-2 is a phase 2, multicohort study evaluating the safety and efficacy of cilta-cel, an anti-BCMA chimeric antigen receptor T therapy, in various myeloma patient populations. Patients in cohort C progressed despite treatment with a proteasome inhibitor, immunomodulatory drug, anti-CD38 antibody, and noncellular anti-BCMA immunotherapy. A single cilta-cel infusion was given after lymphodepletion. The primary end point was minimal residual disease (MRD) negativity at 10-5. Overall, 20 patients were treated (13 ADC exposed; 7 BsAb exposed; 1 in the ADC group also had prior BsAb exposure). Sixteen (80%) were refractory to prior anti-BCMA therapy. At a median follow-up of 11.3 months (range, 0.6-16.0), 7 of 20 (35%) patients were MRD negative (7 of 10 [70.0%] in the MRD-evaluable subset). Overall response rate (95% confidence interval [CI]) was 60.0% (36.1-80.9). Median duration of response and progression-free survival (95% CI) were 11.5 (7.9-not estimable) and 9.1 (1.5-not estimable) months, respectively. The most common adverse events were hematologic. Cytokine release syndrome occurred in 12 (60%) patients (all grade 1-2); 4 had immune effector cell-associated neurotoxicity syndrome (2 had grade 3-4); none had parkinsonism. Seven (35%) patients died (3 of progressive disease, 4 of adverse events [1 treatment related, 3 unrelated]). Cilta-cel induced favorable responses in patients with relapsed/refractory MM and prior exposure to anti-BCMA treatment who had exhausted other therapies. This trial was registered at www.clinicaltrials.gov as NCT04133636.
Effect of SARS-CoV-2 Infection and Infection Severity on Longer-Term Glycemic Control and Weight in People With Type 2 Diabetes
Authors: Rachel Wong, Rohith Vaddavalli, Margaret A. Hall, Monil V. Patel, Carolyn T. Bramante, Elena Casarighi, Steven G. Johnson, Veena Lingam, Joshua D. Miller, Jane Reusch, Mary Saltz, Til Stürmer, Jena S. Tronieri, Kenneth J. Wilkins, John B. Buse, Joel Saltz, Jared D. Huling, Richard Moffitt, Adit Anand, Tellen Bennett, Christopher G. Chute, Peter DeWitt, Michael Evans, Victor Garcia, Kenneth Gersing, Andrew Girvin, Melissa Haendel, Jeremy R. Harper, Janos Hajagos, Stephanie Hong, Emily Pfaff, Jacob Wooldridge, Yun Jae Yoo
Journal: Diabetes Care (2022)

OBJECTIVE To evaluate the association of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severity of infection with longer-term glycemic control and weight in people with type 2 diabetes (T2D) in the U.S. RESEARCH DESIGN AND METHODS We conducted a retrospective cohort study using longitudinal electronic health record data of patients with SARS-CoV-2 infection from the National COVID Cohort Collaborative (N3C). Patients were ≥18 years old with an ICD-10 diagnosis of T2D and at least one HbA1c and weight measurement prior to and after an index date of their first coronavirus disease 2019 (COVID-19) diagnosis or negative SARS-CoV-2 test. We used propensity scores to identify a matched cohort balanced on demographic characteristics, comorbidities, and medications used to treat diabetes. The primary outcome was the postindex average HbA1c and postindex average weight over a 1 year time period beginning 90 days after the index date among patients who did and did not have SARS-CoV-2 infection. Secondary outcomes were postindex average HbA1c and weight in patients who required hospitalization or mechanical ventilation. RESULTS There was no significant difference in the postindex average HbA1c or weight in patients who had SARS-CoV-2 infection compared with control subjects. Mechanical ventilation was associated with a decrease in average HbA1c after COVID-19. CONCLUSIONS In a multicenter cohort of patients in the U.S. with preexisting T2D, there was no significant change in longer-term average HbA1c or weight among patients who had COVID-19. Mechanical ventilation was associated with a decrease in HbA1c after COVID-19.
Tumor immunotherapy boosted by R837 nanocrystals through combining chemotherapy and mild hyperthermia
Authors: Zhengjie Meng, Xue Fang, Bowen Fu, Cheng Qian, Zheng Yang, Yunhao Bai, Xinyue Tao, Haixiao Huang, Chenyu Ma, Wenjun Miao, Hao Ren, Aiyun Wang, Xueming Li
Journal: Journal of Controlled Release (2022)
Blood pressure and childhood obstructive sleep apnea: A systematic review and meta-analysis
Authors: Sizhi Ai, Zhexi Li, Shanshan Wang, Sijing Chen, Joey WY Chan, Chun Ting Au, Yanping Bao, Albert Martin Li, Jihui Zhang, Kate Ching-Ching Chan, Yun-Kwok Wing
Journal: Sleep Medicine Reviews (2022)
Screening for Type 2 Diabetes in Children and Adolescents
Authors: Jill Jin
Journal: JAMA (2022)

US Preventive Services Task Force; Carol M. Mangione, MD, MSPH; Michael J. Barry, MD; Wanda K. Nicholson, MD, MPH, MBA; Michael Cabana, MD, MA, MPH; David Chelmow, MD; Tumaini Rucker Coker, MD, MBA; Karina W. Davidson, PhD, MASc; Esa M. Davis, MD, MPH; Katrina E. Donahue, MD, MPH; Carlos Roberto Jaén, MD, PhD, MS; Martha Kubik, PhD, RN; Li Li, MD, PhD, MPH; Gbenga Ogedegbe, MD, MPH; Lori Pbert, PhD; John M. Ruiz, PhD; James Stevermer, MD, MSPH; Chien-Wen Tseng, MD, MPH, MSEE; John B. Wong, MD
Screening for Prediabetes and Type 2 Diabetes in Children and Adolescents
Authors: Carol M. Mangione, Michael J. Barry, Wanda K. Nicholson, Michael Cabana, David Chelmow, Tumaini Rucker Coker, Karina W. Davidson, Esa M. Davis, Katrina E. Donahue, Carlos Roberto Jaén, Martha Kubik, Li Li, Gbenga Ogedegbe, Lori Pbert, John M. Ruiz, James Stevermer, Chien-Wen Tseng, John B. Wong
Journal: JAMA (2022)

The Centers for Disease Control and Prevention estimates that 210 000 children and adolescents younger than 20 years had diabetes as of 2018; of these, approximately 23 000 had type 2 diabetes. Youth with type 2 diabetes have an increased prevalence of associated chronic comorbid conditions, including hypertension, dyslipidemia, and nonalcoholic fatty liver disease. Data indicate that the incidence of type 2 diabetes is rising; from 2002-2003 to 2014-2015, incidence increased from 9.0 cases per 100 000 children and adolescents to 13.8 cases per 100 000 children and adolescents.The US Preventive Services Task Force (USPSTF) commissioned a review of the evidence on screening for prediabetes and type 2 diabetes in asymptomatic, nonpregnant persons younger than 18 years. This is a new recommendation.Children and adolescents younger than 18 years without known diabetes or prediabetes or symptoms of diabetes or prediabetes.The USPSTF concludes that the evidence is insufficient to assess the balance of benefits and harms of screening for type 2 diabetes in children and adolescents. There is a lack of evidence on the effect of screening for, and early detection and treatment of, type 2 diabetes on health outcomes in youth, and the balance of benefits and harms cannot be determined.The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for type 2 diabetes in children and adolescents. (I statement).
CD11b+CD43hiLy6Clo splenocyte‐derived macrophages exacerbate liver fibrosis via spleen–liver axis
Authors: Shaoying Zhang, Dan Wan, Mengchen Zhu, Guihu Wang, Xurui Zhang, Na Huang, Jian Zhang, Chongyu Zhang, Qi Shang, Chen Zhang, Xi Liu, Fanfan Liang, Chunyan Zhang, Guangyao Kong, Jing Geng, Libo Yao, Shemin Lu, Yongyan Chen, Zongfang Li
Journal: Hepatology (2022)

Background and Aims: Monocyte‐derived macrophages (MoMFs), a dominant population of hepatic macrophages under inflammation, play a crucial role in liver fibrosis progression. The spleen serves as an extra monocyte reservoir in inflammatory conditions; however, the precise mechanisms of involvement of the spleen in the pathogenesis of liver fibrosis remain unclear. Approach and Results: By splenectomy and splenocyte transfusion, it was observed that splenic CD11b + cells accumulated intrahepatically as Ly6C lo MoMFs to exacerbate CCl 4 ‐induced liver fibrosis. The splenocyte migration into the fibrotic liver was further directly visualized by spleen‐specific photoconversion with KikGR mice and confirmed by CD45.1 + /CD45.2 + spleen transplantation. Spleen‐derived CD11b + cells purified from fibrotic livers were then annotated by single‐cell RNA sequencing, and a subtype of CD11b + CD43 hi Ly6C lo splenic monocytes (sM‐1s) was identified, which was markedly expanded in both spleens and livers of mice with liver fibrosis. sM‐1s exhibited mature feature with high expressions of F4/80, produced much ROS, and manifested preferential migration into livers. Once recruited, sM‐1s underwent sequential transformation to sM‐2s (highly expressed Mif , Msr1 , Clec4d , and Cstb ) and then to spleen‐derived macrophages (sMφs) with macrophage features of higher expressions of CX 3 CR1, F4/80, MHC class II, and CD64 in the fibrotic hepatic milieu. Furthermore, sM‐2s and sMφs were demonstrated capable of activating hepatic stellate cells and thus exacerbating liver fibrosis. Conclusions: CD11b + CD43 hi Ly6C lo splenic monocytes migrate into the liver and shift to macrophages, which account for the exacerbation of liver fibrosis. These findings reveal precise mechanisms of spleen–liver axis in hepatic pathogenesis and shed light on the potential of sM‐1 as candidate target for controlling liver diseases.